CN1727319A - Device in category of substitution tricyclo-diterpene-orthodiphenol, preparation method and application - Google Patents
Device in category of substitution tricyclo-diterpene-orthodiphenol, preparation method and application Download PDFInfo
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- CN1727319A CN1727319A CN 200510050874 CN200510050874A CN1727319A CN 1727319 A CN1727319 A CN 1727319A CN 200510050874 CN200510050874 CN 200510050874 CN 200510050874 A CN200510050874 A CN 200510050874A CN 1727319 A CN1727319 A CN 1727319A
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Abstract
An anticancer substituted tricycloditerpene o-biphenol derivative, its preparing process and its application in preventing and treating cancer are disclosed.
Description
Invention field
The invention belongs to organic chemistry, pharmaceutical chemistry and area of pharmacology, particularly, the present invention relates to have toxic device in category of substitution tricyclo-diterpene-orthodiphenol of antitumor cell and its production and use.Through the pharmacologically active test, this compounds has antitumour activity, can expect as the antitumor drug purposes.
Background technology
The inventor finds that the device in category of substitution tricyclo-diterpene-orthodiphenol that the present invention prepares has antineoplastic activity, can expect as the antitumor drug purposes.Finished the present invention thus.
Goal of the invention
The object of the present invention is to provide a series of compounds with antitumour activity.Particularly, the invention provides a kind of the have device in category of substitution tricyclo-diterpene-orthodiphenol shown in formula (1), (2) or its solvate:
Formula (1)
Formula (2)
R wherein
1, R
2Can be to contain substituent benzyl on hydrogen atom or methyl or the aromatic ring; R
3, R
4Can be respectively hydrogen atom, Sauerstoffatom.Another object of the present invention has provided the preparation method of preparation formula (1), (2) compound;
Another object of the present invention has provided the purposes that formula (1), (2) compound are used to prepare antitumor drug.
Summary of the invention
The invention provides a kind of the have device in category of substitution tricyclo-diterpene-orthodiphenol shown in formula (1), (2) or its solvate:
Formula (1)
Formula (2)
R wherein
1, R
2Can be to contain substituent benzyl on hydrogen atom or methyl or the aromatic ring; R
3, R
4Can be respectively hydrogen atom, Sauerstoffatom.
(1)-and 1:(4b β, 8a α)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(1)-and 2:(4b β, 8a α)-2-is to chlorobenzene methoxyl group-3-hydroxyl-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(1)-and 3:(4b β, 8a α)-2-hydroxyl-3-is to chlorobenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(1)-and 4:(4b β, 8a α)-the adjacent fluorobenzene methoxyl group of 2--3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(1)-and 5:(4b β, 8a α)-the adjacent fluorobenzene methoxyl group-4b of 2-hydroxyl-3-, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(1)-and 6:(4b β, 8a α)-2-m-nitro methoxyl group-3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(1)-and 7:(4b β, 8a α)-2-hydroxyl-3-m-nitro methoxyl group-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(1)-and 8:(4b β, 8a α)-2-hydroxyl-4-is to fluorobenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(1)-and 9:(4b β, 8a α)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(1)-and 10:(4b β, 8a α)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9-seven hydrogen-10-carbonyl phenanthrene
(1)-and 11:(4b β, 8a α)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9-seven hydrogen-10-carbonyl phenanthrene
(2)-and 1:(4b β, 8a β)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 2:(4b β, 8a β)-2-benzyloxy-3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a β, 9,10-octahydro phenanthrene
(2)-and 3:(4b β, 8a β)-2-is to methylbenzene methoxyl group-3-hydroxyl-4b β, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 4:(4b β, 8a β)-2-hydroxyl-3-is to methylbenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 5:(4b β, 8a β)-2-hydroxyl-3-is to anisole methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 6:(4b β, 8a β)-2-is to chlorobenzene methoxyl group-3-hydroxyl-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 7:(4b β, 8a β)-2-hydroxyl-3-is to chlorobenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 8:(4b β, 8a β)-the adjacent fluorobenzene methoxyl group of 2--3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 9:(4b β, 8a β)-the adjacent fluorobenzene methoxyl group-4b of 2-hydroxyl-3-, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 10:(4b β, 8a β)-2-O-methoxy benzyloxy-3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 11:(4b β, 8a β)-2-hydroxyl-3-O-methoxy benzyloxy-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 12:(4b β, 8a β)-2-is to fluorobenzene methoxyl group-3-hydroxyl-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 13:(4b β, 8a β)-2-hydroxyl-3-is to fluorobenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 14:(4b β, 8a β)-2-m-nitro methoxyl group-3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 15:(4b β, 8a β)-2-hydroxyl-3-m-nitro methoxyl group-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 16:(4b β, 8a β)-2-is to anisole methoxyl group-3-hydroxyl-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene
(2)-and 17:(4b β, 8a β)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10 octahydro phenanthrene
(2)-and 18:(4b β, 8a β)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9-seven hydrogen-10-carbonyl phenanthrene
(2)-and 19:(4b β, 8a β)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a-six hydrogen-9,10-dicarbapentaborane phenanthrene
(2)-and 20:(4b β, 8a β)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9-seven hydrogen-10-carbonyl phenanthrene
(2)-and 21:(4b β, 8a β)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a-six hydrogen-9,10-dicarbapentaborane phenanthrene
Each structural formula of compound:
The present invention also provides the preparation method of a kind of formula (1), (2) compound, and the operational path feature of this synthetic route is:
Experiment of the present invention shows that also compound described in its preparation intermediate of formula (1) and formula (2) to the cytotoxic activity of strain of Hela knurl and the strain of A549 knurl, shows that this compound might develop into antitumor drug.
Its preparation intermediate or its pharmacologically acceptable salt of formula of the present invention (1) and formula (2) compound or its solvate can combine with auxiliary material or carrier pharmaceutically commonly used, have anti-tumor activity and can be used for anti-cancer pharmaceutical composition thereby prepare.Above-mentioned various kinds of drug composition can adopt drug forms such as injection, tablet or capsule.
Further specify the present invention below by embodiment.Embodiment has provided synthetic and the dependency structure appraising datum and the part activity data of representative new compound.Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention.
Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment
Preparation example
Preparation example 1: the preparation of Compound I-0 ((±)-α-ring citric acid):
In 300ml toluene, add 25g85% geranic acid (126.5mmol), be warming up to 100 ℃ after the dissolving fully, drip 85% phosphatase 11 .6ml, stirred 2 hours, be cooled to room temperature, add sodium bicarbonate 3.1g, stirred 0.5 hour, and filtered out solid, solution with water is washed (100ml * 2), tell organic phase, water transfers to PH ≈ 5 with 2M hydrochloric acid, with ether extraction (50ml * 3), merges organic phase, anhydrous sodium sulfate drying, suction filtration, rotary evaporation removes and desolvates, and placement is spent the night, suction filtration, solid washs with a small amount of normal hexane, obtains white solid 18.6g, productive rate 74.4%.
Preparation example 2: the preparation of Compound I-1 ((±)-α-cyclocitral)
18gI-0 (109.7mmol) is dissolved in the 300ml acetone, adds salt of wormwood 16g (115.9mmol), stirs 20 minutes, drip the 17.6g methyl-sulfate, stirred 4 hours under the room temperature, underpressure distillation boils off solvent, adds 200ml water, dissolving back ether extraction (100ml * 3), anhydrous sodium sulfate drying filters the evaporate to dryness ether, get colourless liquid 15.6g, N
2Down, this liquid carefully is added dropwise to LiAlH
4The anhydrous diethyl ether suspension liquid in, stirred under the room temperature 4 hours, ice bath is careful down to add the 200ml shrend reaction of going out, filter, filter residue washs with ether, and filtrate is told water, with extracted with diethyl ether (75ml * 3), merge organic phase, with saturated common salt water washing (50ml3), anhydrous sodium sulfate drying, filter, the evaporate to dryness ether gets colourless liquid 13.4g, this liquid is dissolved in the 300ml methylene dichloride, be cooled to-5 ℃, add the PCC of 15g new system, keep temperature to stir 5 hours, carefully pour out solution, residue washed with dichloromethane 3 times merge organic phase, washing (100ml * 2), anhydrous sodium sulfate drying, filter, the evaporate to dryness methylene dichloride, remaining suspension liquid filters, filter residue washs with ether, merge organic phase, the evaporate to dryness ether gets yellow-green liquid 11g, silica gel column chromatography (petrol ether/ethyl acetate: 200/1) obtain colourless liquid 6.5 grams, yield 40.1%.
Preparation example 3: the preparation of Compound I-2 (1,2-dimethoxy-4 '-(Z-2-(2,6,6-trimethylammonium-2-cyclohexenyl) vinyl) benzene)
N
2Down, room temperature, 17.6g chlorination 1, be added dropwise to 20.3ml2Mn-BuLi solution in 2-dimethoxy benzene methylene radical triphenyl phosphorus and the 300ml THF suspension liquid, stirred 1 hour, system is the scarlet settled solution, keeps room temperature to be added dropwise to 6.5gI-1, stirred 5 hours, add saturated aqueous ammonium chloride 200ml cancellation reaction, tell organic layer, water layer extracted with diethyl ether (100ml3), merge organic phase, the saturated common salt water washing, anhydrous sodium sulfate drying, rotary evaporation removes and desolvates, silica gel column chromatography (petrol ether/ethyl acetate: 150/1) obtain colourless oil liquid 7.8 grams, yield 65.1%.
Embodiment 1,2: compound (1)-9 ((4b β, 8a α)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene) and (2)-17 ((4b β, 8a β)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene) preparation
7.5gI-2 be dissolved in the 300ml anhydrous diethyl ether N
2Air is fallen in exchange, adds Pd/C1.5g, H
2N is fallen in exchange
2, stirred 30 minutes, feed N
2Filter, the solution solvent evaporated, get the 7.4g colourless oil liquid, be dissolved in the 300ml methylene dichloride, add boron trifluoride diethyl etherate 2.2g, stirred 30 minutes, left standstill 24 hours, add saturated sodium bicarbonate solution and transfer to PH=8, separate organic phase, water dichloromethane extraction (50ml * 3), merge the organic phase anhydrous sodium sulfate drying, suction filtration, underpressure distillation removes and desolvates, silica gel column chromatography (petrol ether/ethyl acetate: 200/1) get colourless oil liquid (1)-93.3g, get colourless oil liquid (2)-173.5g, total recovery 90.7%.
Embodiment 3: the preparation of compound (1)-1 ((4b β, 8a α)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene)
Compound (1)-8100mg (0.35mmol) is dissolved in the 30ml methylene dichloride, splashes into the 0.52mmol boron tribromide under the ice-water bath condition, keeps thermotonus 1 hour.Add saturated sodium bicarbonate and transfer to PH=8, tell organic phase, water merges organic phase, saturated common salt water washing (15ml2), anhydrous sodium sulfate drying with dichloromethane extraction (20ml * 3).Rotary evaporation removes the rear pillar chromatography that desolvates (petrol ether/ethyl acetate: 10/1) get white solid 76mg, productive rate 84.2%.
Embodiment 4, and 5:(1)-2 ((4b β, 8a α)-2-is to chlorobenzene methoxyl group-3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene) and (1)-3 ((4b β, 8a α)-and 2-hydroxyl-3-is to chlorobenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene) preparation
62.8mg is dissolved in the 5ml acetone the chlorine bromobenzyl, adds the 48mg sodium iodide, stirred 15 minutes, add 51.2mg salt of wormwood, 80mg compound (1)-1 (0.19mmol), reflux and stirred 5 hours, cooling, underpressure distillation evaporate to dryness acetone adds 10ml water and 10ml ether and shakes up, and tells organic phase, water layer merges organic phase with ether extraction (10ml * 3), with the saturated common salt washing once, anhydrous sodium sulfate drying, suction filtration, rotary evaporation removes and desolvates, column chromatography (petrol ether/ethyl acetate: 50/1)
(1)-2 (colourless oil liquid) 45mg, productive rate 38.1%, (1)-3 (colourless oil liquid) 49mg, productive rate 38.2%.
Prepare following table one illustrated embodiment 1-26 compound according to similar approach with above preparation example 1-3 and embodiment 1-5:
Table one:
| Embodiment number | Compound number | 8a hydrogen configuration | R | ESIMS(M+Na) + |
| 1 | (1)-9 | α | R 1＝R 2=methyl, R 3＝R 4=hydrogen atom | 310.9 |
| 2 | (2)-17 | β | R 1＝R 2=methyl, R 3＝R 4=hydrogen atom | 311.2 |
| 3 | (1)-1 | α | R 1＝R 2＝R 3＝R 4=hydrogen atom | 283.0 |
| 4 | (1)-2 | α | R 2＝R 3＝R 4=hydrogen atom, R 1=rubigan methyl | 407.3 |
| 5 | (1)-3 | α | R 1＝R 3＝R 4=hydrogen atom, R 2=rubigan methyl | 407.2 |
| 6 | (1)-4 | α | R 2＝R 3＝R 4=hydrogen atom, R 1=adjacent fluorophenyl methyl | 391.3 |
| 7 | (1)-5 | α | R 1＝R 3＝R 4=hydrogen atom, R 2=adjacent fluorophenyl methyl | 391.1 |
| 8 | (1)-6 | α | R 2＝R 3＝R 4=hydrogen atom, R 1=m-nitro ylmethyl | 417.9 |
| 9 | (1)-7 | α | R 1＝R 3＝R 4=hydrogen atom, R 2=m-nitro ylmethyl | 418.2 |
| 10 | (1)-8 | α | R 2＝R 3＝R 4=hydrogen atom, R 1=to fluorophenyl methyl | 391.4 |
| 11 | (2)-1 | β | R 1＝R 2＝R 3＝R 4=hydrogen atom | 283.0 |
| 12 | (2)-2 | β | R 2＝R 3＝R 4=hydrogen atom, R 1=phenyl methyl | 373.2 |
| 13 | (2)-3 | β | R 2＝R 3＝R 4=hydrogen atom, R 1=p-methylphenyl methyl | 387.2 |
| 14 | (2)-4 | β | R 1＝R 3＝R 4=hydrogen atom, R 2=p-methylphenyl methyl | 387.3 |
| 15 | (2)-5 | β | R 1＝R 3＝R 4=hydrogen atom, R 2=p-methoxyphenyl methyl | 403.1 |
| 16 | (2)-6 | β | R 2＝R 3＝R 4=hydrogen atom, R 1=rubigan methyl | 407.2 |
| 17 | (2)-7 | β | R 1＝R 3＝R 4=hydrogen atom, R 2=rubigan methyl | 407.1 |
| 18 | (2)-8 | β | R 2＝R 3＝R 4=hydrogen atom, R 1=adjacent fluorophenyl methyl | 391.4 |
| 19 | (2)-9 | β | R 1＝R 3＝R 4=hydrogen atom, R 2=adjacent fluorophenyl methyl | 391.3 |
| 20 | (2)-10 | β | R 2＝R 3＝R 4=hydrogen atom, R 1=o-methoxyphenyl methyl | 403.2 |
| 21 | (2)-11 | β | R 1＝R 3＝R 4=hydrogen atom, R 2=o-methoxyphenyl methyl | 403.1 |
| 22 | (2)-12 | β | R 2＝R 3＝R 4=hydrogen atom, R 1=to fluorophenyl methyl | 391.3 |
| 23 | (2)-13 | β | R 1＝R 3＝R 4=hydrogen atom, R 2=to fluorophenyl methyl | 391.2 |
| 24 | (2)-14 | β | R 2＝R 3＝R 4=hydrogen atom, R 1=m-nitro ylmethyl | 418.1 |
| 25 | (2)-15 | β | R 1＝R 3＝R 4=hydrogen atom, R 2=m-nitro ylmethyl | 417.8 |
| 26 | (2)-16 | β | R 2＝R 3＝R 4=hydrogen atom, R 1=p-methoxyphenyl methyl | 403.2 |
What list below is the physicochemical data of each compound in the table one:
(1)-and 1:(4b β, 8a α)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, white solid, m.p.83-85 ℃ (re-crystallizing in ethyl acetate), Rf (ethyl acetate/petroleum ether: 1/8) 0.30; 1H-NMR (500MHz, CDCl3, δ ppm): 0.92 (s, 3H, H-8 β-CH3), 0.95 (s, 3H, H-8 α-CH
3), 1.19 (s, 3H, H-4b-CH
3), 1.25～1.73 (m, 8H, H-5 ', 6,7,8 α, 9), 2.24 (m, 1H, H-5 "), 2.83 (m, 2H, H-10), 6.52 (s, 1H, H-1), 6.77 (s, 1H, H-4).
(1)-and 2:(4b β, 8a α)-2-is to chlorobenzene methoxyl group-3-hydroxyl-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.35;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.91 (s, 3H, H-8 β-CH3), 0.94 (s, 3H, H-8 α-CH
3), 1.16 (s, 3H, H-4b-CH
3), 1.24～1.84 (m, 8H, H-5 ', 6,7,8 α, 9), 2.19 (m, 1H, H-5 "), 2.79 (m, 2H, H-10), 5.01 (s, 2H, H-OCH
2), 6.55 (s, 1H, H-1), 6.85 (s, 1H, H-4), 7.35 (m, 4H, H-C
6H
4).
(1)-and 3:(4b β, 8a α)-2-hydroxyl-3-is to chlorobenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.91 (s, 3H, H-8 β-CH3), 0.94 (s, 3H, H-8 α-CH
3), 1.14 (s, 3H, H-4b-CH
3), 1.28～1.74 (m, 8H, H-5 ', 6,7,8 α, 9), 2.12 (m, 1H, H-5 "), 2.80 (m, 2H, H-10), 5.01 (s, 2H, H-OCH
2), 6.60 (s, 1H, H-1), 6.76 (s, 1H, H-4), 7.36 (m, 4H, H-C
6H
4).
(1)-and 4:(4b β, 8a α)-the adjacent fluorobenzene methoxyl group of 2--3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.32;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.91 (s, 3H, H-8 β-CH3), 0.94 (s, 3H, H-8 α-CH
3), 1.16 (s, 3H, H-4b-CH
3), 1.25～1.84 (m, 8H, H-5 ', 6,7,8 α, 9), 2.19 (m, 1H, H-5 "), 2.81 (m, 2H, H-10), 5.12 (s, 2H, H-OCH
2), 6.62 (s, 1H, H-1), 6.85 (s, 1H, H-4), 7.08～7.45 (m, 4H, H-C
6H
4).
(1)-and 5:(4b β, 8a α)-the adjacent fluorobenzene methoxyl group-4b of 2-hydroxyl-3-, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.28;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.92 (s, 3H, H-8 β-CH3), 0.94 (s, 3H, H-8 α-CH
3), 1.15 (s, 3H, H-4b-CH
3), 1.23～1.83 (m, 8H, H-5 ', 6,7,8 α, 9), 2.17 (m, 1H, H-5 "), 2.81 (m, 2H, H-10), 5.12 (s, 2H, H-OCH
2), 6.59 (s, 1H, H-1), 6.84 (s, 1H, H-4), 7.08～7.45 (m, 4H, H-C
6H
4).
(1)-and 6:(4b β, 8a α)-2-m-nitro methoxyl group-3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/10) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.91 (s, 3H, H-8 β-CH3), 0.95 (s, 3H, H-8 α-CH
3), 1.14 (s, 3H, H-4b-CH
3), 1.25～1.81 (m, 8H, H-5 ', 6,7,8 α, 9), 2.18 (m, 1H, H-5 "), 2.79 (m, 2H, H-10), 5.16 (s, 2H, H-OCH
2), 6.54 (s, 1H, H-1), 6.87 (s, 1H, H-4), 7.57～8.28 (m, 4H, H-C
6H
4).
(1)-and 7:(4b β, 8a α)-2-hydroxyl-3-m-nitro methoxyl group-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.91 (s, 3H, H-8 β-CH3), 0.94 (s, 3H, H-8 α-CH
3), 1.16 (s, 3H, H-4b-CH
3), 1.25～1.84 (m, 8H, H-5 ', 6,7,8 α, 9), 2.19 (m, 1H, H-5 "), 2.80 (m, 2H, H-10), 5.01 (s, 2H, H-OCH
2), 6.57 (s, 1H, H-1), 6.85 (s, 1H, H-4), 7.07～7.39 (m, 4H, H-C
6H
4).
(1)-and 8:(4b β, 8a α)-2-hydroxyl-3-is to fluorobenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/10) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.91 (s, 3H, H-8 β-CH3), 0.95 (s, 3H, H-8 α-CH
3), 1.14 (s, 3H, H-4b-CH
3), 1.25～1.78 (m, 8H, H-5 ', 6,7,8 α, 9), 2.13 (m, 1H, H-5 "), 2.78 (m, 2H, H-10), 5.17 (s, 2H, H-OCH
2), 6.62 (s, 1H, H-1), 6.77 (s, 1H, H-4), 7.57～8.29 (m, 4H, H-C
6H
4).
(1)-and 9:(4b β, 8a α)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.45;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.92 (s, 3H, H-8 β-CH3), 0.95 (s, 3H, H8 α-CH
3), 1.19 (s, 3H, H-4b-CH
3), 1.27～1.73 (m, 8H, H-5 ', 6,7,8 α, 9), 2.24 (m, 1H, H-5 "), 2.83 (m, 2H, H-10), 3.83 (s, 3H, H-OMe), 3.84 (s, 3H, H-OMe), 6.52 (s, 1H, H-1), 6.77 (s, 1H, H-4).
(2)-and 1:(4b β, 8a β)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, white solid, m.p.81-83 ℃ (re-crystallizing in ethyl acetate), Rf (ethyl acetate/petroleum ether: 1/8) 0.30; 1H-NMR (500MHz, CDCl3, δ ppm): 0.41 (s, 3H, H-8 β-CH3), 0.91 (s, 3H, H-8 α-CH
3), 1.11 (s, 3H, H-4b-CH
3), 1.25～1.47 (m, 6H, H-5 ', 6,7,8 α), 1.92 (m, 1H, H-9 "), 2.14 (m, 1H, H-9 '), 2.28 (m, 1H, H-5 "), 2.76 (m, 2H, H-10), 6.53 (s, 1H, H-1), 6.79 (s, 1H, H-4).
(2)-and 2:(4b β, 8a β)-2-benzyloxy-3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a β, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.32;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.37 (s, 3H, H-8 β-CH3), 0.91 (s, 3H, H-8 α-CH
3), 1.12 (s, 3H, H-4b-CH
3), 1.26～1.40 (m, 6H, H-5 ', 6,7,8 α), 1.93 (m, 1H, H-9 "), 2.14 (m, 1H, H-9 '), 2.25 (m, 1H, H-5 "), 2.77 (m, 2H, H-10), 6.60 (s, 1H, H-1), 6.81 (s, 1H, H-4), 7.38 (m, 5H, H=C
6H
5).
(2)-and 3:(4b β, 8a β)-2-is to methylbenzene methoxyl group-3-hydroxyl-4b β, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.32;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.43 (s, 3H, H-8 β-CH3), 0.92 (s, 3H, H-8 α-CH
3), 1.13 (s, 3H, H-4b-CH
3), 1.24～1.47 (m, 6H, H-5 ', 6,7,8 α), 1.94 (m, 1H, H-9 "), 2.16 (m, 1H, H-9 '), 2.31 (m, 1H, H-5 "), 2.37 (s, 3H, H-Ph-CH
3), 2.80 (m, 2H, H-10), 5.00 (s, 2H, H-OCH
2), 6.60 (s, 1H, H-1), 6.88 (s, 1H, H-4), 7.19 (d, 2H, J=8.0Hz, H=C
6H
4), 7.30 (d, 2H, J=8.0Hz, H=C
6H
4).
(2)-and 4:(4b β, 8a β)-2-hydroxyl-3-is to methylbenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.38 (s, 3H, H-8 β-CH3), 0.92 (s, 3H, H-8 α-CH
3), 1.12 (s, 3H, H-4b-CH
3), 1.26～1.40 (m, 6H, H-5 ', 6,7,8 α), 1.98 (m, 1H, H-9 "), 2.14 (m, 1H, H-9 '), 2.26 (m, 1H, H-5 "), 2.36 (s, 3H, H-Ph-CH
3), 2.77 (m, 2H, H-10), 5.02 (s, 2H, H-OCH
2), 6.59 (s, 1H, H-1), 6.82 (s, 1H, H-4), 7.18 (d, 2H, J=7.5Hz, H=C
6H
4), 7.30 (d, 2H, J=7.5Hz, H=C
6H
4).
(2)-and 5:(4b β, 8a β)-2-hydroxyl-3-is to anisole methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.25;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.40 (s, 3H, H-8 β-CH3), 0.93 (s, 3H, H-8 α-CH
3), 1.14 (s, 3H, H-4b-CH
3), 1.27～1.42 (m, 6H, H-5 ', 6,7,8 α), 1.96 (m, 1H, H-9 "), 2.22 (m, 1H, H-9 '), 2.26 (m, 1H, H-5 "), 2.78 (m, 2H, H-10), 3.83 (s, 6H, H-OCH
3), 5.00 (s, 4H, H-OCH
2), 6.60 (s, 1H, H-1), 6.84 (s, 1H, H-4), 6.92 (d, 4H, J=8.5Hz, H=C
6H
4), 7.35 (d, 4H, J=8.5Hz, H=C
6H
4).
(2)-and 6:(4b β, 8a β)-2-is to chlorobenzene methoxyl group-3-hydroxyl-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.42 (s, 3H, H-8 β-CH3), 0.93 (s, 3H, H-8 α-CH
3), 1.14 (s, 3H, H-4b-CH
3), 1.27～1.47 (m, 6H, H-5 ', 6,7,8 α), 1.95 (m, 1H, H-9 "), 2.16 (m, 1H, H-9 '), 2.32 (m, 1H, H-5 "), 2.80 (m, 2H, H-10), 5.01 (s, 2H, H-OCH
2), 6.57 (s, 1H, H-1), 6.90 (s, 1H, H-4), 7.36 (m, 4H, H=C
6H
4).
(2)-and 7:(4b β, 8a β)-2-hydroxyl-3-is to chlorobenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.25; H-NMR (500MHz, CDCl
3, δ ppm): 0.36 (s, 3H, H-8 β-CH3), 0.92 (s, 3H, H-8 α-CH
3), 1.11 (s, 3H, H-4b-CH
3), 1.26～1.40 (m, 6H, H-5 ', 6,7,8 α), 1.92 (m, 1H, H-9 "), 2.13 (m, 1H, H-9 '), 2.22 (m, 1H, H-5 "), 2.76 (m, 2H, H-10), 5.04 (s, 2H, H-OCH
2), 6.60 (s, 1H, H-1), 6.76 (s, 1H, H-4), 7.34 (m, 4H, H=C
6H
4).
(2)-and 8:(4b β, 8a β)-the adjacent fluorobenzene methoxyl group of 2--3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, pale yellow oily liquid body, Rf (ethyl acetate/petroleum ether: 1/15) 0.25;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.42 (s, 3H, H-8 β-CH3), 0.92 (s, 3H, H-8 α-CH
3), 1.13 (s, 3H, H-4b-CH
3), 1.26～1.47 (m, 6H, H-5 ', 6,7,8 α), 1.94 (m, 1H, H-9 "), 2.16 (m, 1H, H-9 '), 2.31 (m, 1H, H-5 "), 2.80 (m, 2H, H-10), 5.10 (s, 2H, H-OCH
2), 6.63 (s, 1H, H-1), 6.88 (s, 1H, H-4), 7.08～7.45 (m, 4H, H=C
6H
4).
(2)-and 9:(4b β, 8a β)-the adjacent fluorobenzene methoxyl group-4b of 2-hydroxyl-3-, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, pale yellow oily liquid body, Rf (ethyl acetate/petroleum ether: 1/15) 0.27;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.37 (s, 3H, H-8 β-CH3), 0.91 (s, 3H, H-8 α-CH
3), 1.12 (s, 3H, H-4b-CH
3), 1.25～1.42 (m, 6H, H-5 ', 6,7,8 α), 1.93 (m, 1H, H-9 "), 2.15 (m, 1H, H-9 '), 2.28 (m, 1H, H-5 "), 2.77 (m, 2H, H-10), 5.16 (s, 2H, H-OCH
2), 6.60 (s, 1H, H-1), 6.85 (s, 1H, H-4), 7.08～7.45 (m, 4H, H=C
6H
4).
(2)-and 10:(4b β, 8a β)-2-O-methoxy benzyloxy-3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, pale yellow oily liquid body, Rf (ethyl acetate/petroleum ether: 1/15) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.37 (s, 3H, H-8 β-CH
3), 0.92 (s, 3H, H-8 α-CH
3), 1.13 (s, 3H, H-4b-CH
3), 1.26～1.42 (m, 6H, H-5 ', 6,7,8 α), 1.92 (m, 1H, H-9 "), 2.14 (m, 1H, H-9 '), 2.29 (m, 1H, H-5 "), 2.79 (m, 2H, H-10), 5.03 (s, 2H, H-OCH
2), 6.60 (s, 1H, H-1), 6.93 (s, 1H, H-4), 6.93～7.36 (m, 4H, H=C
6H
4).
(2)-and 11:(4b β, 8a β)-2-hydroxyl-3-O-methoxy benzyloxy-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, pale yellow oily liquid body, Rf (ethyl acetate/petroleum ether: 1/15) 0.33;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.42 (s, 3H, H-8 β-CH3), 0.92 (s, 3H, H-8 α-CH
3), 1.14 (s, 3H, H-4b-CH
3), 1.26～1.41 (m, 6H, H-5 ', 6,7,8 α), 1.94 (m, 1H, H-9 "), 2.15 (m, 1H, H-9 '), 2.31 (m, 1H, H-5 "), 2.79 (m, 2H, H-10), 5.02 (s, 2H, H-OCH
2), 6.68 (s, 1H, H-1), 6.88 (s, 1H, H-4), 6.92～7.37 (m, 4H, H=C
6H
4).
(2)-and 12:(4b β, 8a β)-2-is to fluorobenzene methoxyl group-3-hydroxyl-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.42 (s, 3H, H-8 β-CH3), 0.92 (s, 3H, H-8 α-CH
3), 1.13 (s, 3H, H-4b-CH
3), 1.26～1.49 (m, 6H, H-5 ', 6,7,8 α), 1.96 (m, 1H, H-9 "), 2.16 (m, 1H, H-9 '), 2.32 (m, 1H, H-5 "), 2.78 (m, 2H, H-10), 5.00 (s, 2H, H-OCH
2), 6.57 (s, 1H, H-1), 6.88 (s, 1H, H-4), 7.05～7.39 (m, 4H, H=C
6H
4).
(2)-and 13:(4b β, 8a β)-2-hydroxyl-3-is to fluorobenzene methoxyl group-4b, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.37 (s, 3H, H-8 β-CH3), 0.94 (s, 3H, H-8 α-CH
3), 1.12 (s, 3H, H-4b-CH
3), 1.26～1.40 (m, 6H, H-5 ', 6,7,8 α), 1.93 (m, 1H, H-9 "), 2.17 (m, 1H, H-9 '), 2.24 (m, 1H, H-5 "), 2.77 (m, 2H, H-10), 5.04 (s, 2H, H-OCH
2), 6.60 (s, 1H, H-1), 6.78 (s, 1H, H-4), 7.04～7.39 (m, 4H, H=C
6H
4).
(2)-and 14:(4b β, 8a β)-2-m-nitro methoxyl group-3-hydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, pale yellow oily liquid body, Rf (ethyl acetate/petroleum ether: 1/10) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.39 (s, 3H, H-8 β-CH3), 0.91 (s, 3H, H-8 α-CH3), 1.17 (s, 3H, H-4b-CH3), 1.23～1.41 (m, 6H, H-5 ', 6,7,8 α), 1.96 (m, 1H, H-9 "), 2.10 (m, 1H; H-9 '), 2.25 (m, 1H, H-5 "), 2.81 (m, 2H, H-10), 5.03 (s, 2H, H-OCH2), 6.60 (s, 1H, H-1), 6.87 (s, 1H, H-4), 7.12～7.68 (m, 4H, H=C6H4).
(2)-and 15:(4b β, 8a β)-2-hydroxyl-3-m-nitro methoxyl group-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/10) 0.33; 1H-NMR (500MHz, CDCl3, δ ppm): 0.41 (s, 3H, H-8 β-CH3), 0.95 (s, 3H, H-8 α-CH3), 1.17 (s, 3H, H-4b-CH3), 1.24～1.41 (m, 6H, H-5 ', 6,7,8 α), 1.93 (m, 1H, H-9 "), 2.17 (m; 1H, H-9 '), 2.29 (m, 1H, H-5 "), 2.82 (m, 2H, H-10), 5.05 (s, 2H, H-OCH2), 6.64 (s, 1H, H-1), 6.86 (s, 1H, H-4), 7.09～7.64 (m, 4H, H=C6H4).
(2)-and 16:(4b β, 8a β)-2-is to anisole methoxyl group-3-hydroxyl-4b β, and 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/15) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.45 (s, 3H, H-8 β-CH3), 0.94 (s, 3H, H-8 α-CH
3), 1.15 (s, 3H, H-4b-CH
3), 1.28～1.44 (m, 6H, H-5 ', 6,7,8 α), 1.97 (m, 1H, H-9 "), 2.24 (m, 1H, H-9 '), 2.27 (m, 1H, H-5 "), 2.82 (m, 2H, H-10), 3.84 (s, 3H, H-OCH
3), 4.97 (s, 2H, H-OCH
2), 6.63 (s, 1H, H-1), 6.90 (s, 1H, H-4), 6.94 (d, 2H, J=8.5Hz, H=C
6H
4), 7.35 (d, 2H, J=8.5Hz, H=C
6H
4).
(2)-and 17:(4b β, 8a β)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9,10-octahydro phenanthrene, colourless oil liquid, Rf (ethyl acetate/petroleum ether: 1/8) 0.30;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.41 (s, 3H, H-8 β-CH3), 0.93 (s, 3H, H-8 α-CH
3), 1.15 (s, 3H, H-4b-CH
3), 1.28～1.45 (m, 6H, H-5 ', 6,7,8 α), 1.92 (m, 1H, H-9 "), 2.12 (m, 1H, H-9 '), 2.27 (m, 1H, H-5 "), 2.81 (m, 2H, H-10), 3.83 (s, 3H, H-OCH
3), 3.860 (s, 3H, H-OCH
3), 6.53 (s, 1H, H-1), 6.79 (s, 1H, H-4).
Embodiment 27,28:(2)-18 ((4b β, 8a β)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9-seven hydrogen-10-carbonyl phenanthrene) and (2)-19 ((4b β, 8a β)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a-six hydrogen-9,10-dicarbapentaborane phenanthrene) preparation
100mg (1)-8 is dissolved in the 10ml methylene dichloride, add 250mgPCC under the room temperature, stirred 1 hour, pour in the 50g trash ice, saturated sodium bicarbonate solution transfers to neutrality, with dichloromethane extraction (50ml * 3), merge organic phase, with the saturated common salt washing once, anhydrous sodium sulfate drying, suction filtration, rotary evaporation removes and desolvates, column chromatography (sherwood oil/chloroform/ethyl acetate: 20/20/1) get (2)-18 (white solid) 45mg, productive rate 43.2%, get (2)-19 (yellow solid) 25mg, productive rate 22.8%.
Embodiment 29:(1)-10 the preparation of ((4b β, 8a α)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9-seven hydrogen-10-carbonyl phenanthrene)
Compound (1)-930mg (0.11mmol) is dissolved in the 10ml methylene dichloride, splashes into the 0.18mmol boron tribromide under the ice-water bath condition, keeps thermotonus 3 hours.Add saturated sodium bicarbonate and transfer to PH=8, tell organic phase, water merges organic phase, saturated common salt water washing (5ml * 2), anhydrous sodium sulfate drying with dichloromethane extraction (5ml * 3).Rotary evaporation removes the rear pillar chromatography that desolvates (petrol ether/ethyl acetate: 5/1) get white solid 23mg, productive rate 84.1%.
Prepare following table two illustrated embodiment 27-33 compounds according to similar approach with above embodiment 27-29:
Table two:
| Embodiment number | Compound number | 8a hydrogen configuration | R | ESIMS(M+Na) + |
| 27 | (2)-18 | β | R 1＝R 2=methoxyl group, R 3=Sauerstoffatom, R 4=hydrogen atom | 325.1 |
| 28 | (2)-19 | β | R 1＝R 2=methoxyl group, R 4＝R 3=Sauerstoffatom | 339.2 |
| 29 | (1)-11 | α | R 1＝R 2＝R 4=hydrogen atom, R 3=Sauerstoffatom | 297.1 |
| 30 | (1)-10 | α | R 1＝R 2=methoxyl group, R 3=Sauerstoffatom, R 4=hydrogen atom | 325.3 |
| 31 | (2)-20 | β | R＝R 2＝R 4=hydrogen atom, R 3=Sauerstoffatom | 297.2 |
| 32 | (2)-21 | β | R 1＝R 2=hydrogen atom, R 4＝R 3=Sauerstoffatom | 310.9 |
What list below is the physicochemical data of each compound in the table one:
(1)-and 10:(4b β, 8a α)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9-seven hydrogen-10-carbonyl phenanthrene, white solid, m.p.95-98 ℃ (re-crystallizing in ethyl acetate), Rf (ethyl acetate/petroleum ether: 1/6) 0.40:1H-NMR (500MHz, CDCl3, δ ppm): 0.95 (s, 3H, H-8 β-CH3), 1.01 (s, 3H, H-8 α-CH
3), 1.26 (s3H, H-4b-CH
3), 1.26～1.89 (m, 6H, H-5 ', 6,7,8a), 2.26 (d, 1H, J=7.5Hz, H-5 "), 2.62～2.99 (d, 2H, H-9), 3.91 (s, 3H, H-OMe), 3.97 (s, 3H, H-OMe), 6.82 (s, 1H, H-1), 7.51 (s, 1H, H-4).
(1)-and 11:(4b β, 8a α)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9-seven hydrogen-10-carbonyl phenanthrene, white solid, m.p.117-119 ℃ (re-crystallizing in ethyl acetate), Rf (ethyl acetate/petroleum ether: 1/4) 0.35; H-NMR (500 MHz, CDCl
3, δ ppm): 0.95 (s, 3H, H-8 β-CH3), 1.03 (s, 3H, H-8 α-CH
3), 1.27 (s, 3H, H-4b-CH
3), 1.28～1.89 (m, 6H, H-5 ', 6,7,8a), 2.25 (d, 1H, J=7.5Hz, H-5 "), 2.61～2.95 (d, 2H, H-9), 6.82 (s, 1H, H-1), 7.51 (s, 1H, H-4).
(2)-and 18:(4b β, 8a β)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9-seven hydrogen-10-carbonyl phenanthrene, yellow solid, m.p.94-96 ℃ (re-crystallizing in ethyl acetate), Rf (ethyl acetate/petroleum ether: 1/6) 0.25;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.32 (s, 3H, H-8 β-CH3), 0.94 (s, 3H, H-8 α-CH
3), 1.26 (s, 3H, H-4b-CH
3), 1.29～1.49 (m, 5H, H-5 ', 6,7), 1.84 (d, 1H, J=6.0Hz, H-8a), 2.43 (d, 1H, J=7.5Hz, H-5 "), 2.77 (d, 1H, J=19.0Hz, H-9 "), 2.99 (dd, 1H, J
Greatly=19.0Hz, J
Little=6.4Hz, H-9 '), 3.92 (s, 3H, H-OCH
3), 3.97 (s, 3H, H-OCH
3), 6.80 (s, 1H, H-1), 7.54 (s, 1H, H-4).
(2)-and 19:(4b β, 8a β)-2,3-dimethoxy-4 ' b, 8,8-trimethylammonium-4b, 5,6,7,8,8a-six hydrogen-9,10-dicarbapentaborane phenanthrene, white solid, m.p.105-108 ℃ (re-crystallizing in ethyl acetate), Rf (ethyl acetate/petroleum ether: 1/6) 0.40;
1H-NMR (500MHz, CDCl
3, δ ppm): 0.45 (s, 3H, H-8 β-CH3), 0.98 (s, 3H, H-8 α-CH
3), 1.25 (s, 3H, H-4b-CH
3), 1.35～1.61 (m, 5H, H-5 ', 6,7), 2.52 (d, 1H, J=14.5Hz, H-5 "), 2.99 (s, 1H, H-5a), 3.96 (s, 3H, H-OCH
3), 4.03 (s, 3H, H-OCH
3), 6.87 (s, 1H, H-1), 7.60 (s, 1H, H-4).
(2)-and 20:(4b β, 8a β)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a, 9-seven hydrogen-10-carbonyl phenanthrene, yellow solid, m.p.126-128 ℃ (re-crystallizing in ethyl acetate), Rf (ethyl acetate/petroleum ether: 1/2) 0.40; 1H-NMR (500MHz, CDCl3, δ ppm): 0.33 (s, 3H, H-8 β-CH3), 0.96 (s, 3H, H-8 α-CH
3), 1.25 (s, 3H, H-4b-CH
3), 1.27～1.50 (m, 5H, H-5 ', 6,7), 1.83 (d, 1H, J=6.0Hz, H-8a), 2.45 (d, 1H, J=7.5Hz, H-5 "), 2.78 (d, 1H, J=19.0Hz, H-9 "), 2.99 (dd, 1H, J
Greatly=19.0Hz, J
Little=6.4Hz, H-9 '), 6.80 (s, 1H, H-1), 7.54 (s, 1H, H-4).
(2)-and 21:(4b β, 8a β)-2,3-dihydroxyl-4b, 8,8-trimethylammonium-4b, 5,6,7,8,8a-six hydrogen-9,10-dicarbapentaborane phenanthrene, white solid, m.p.147-149 ℃ (re-crystallizing in ethyl acetate), Rf (ethyl acetate/petroleum ether: 1/6) 0.40; 1H-NMR (500MHz, CDCl3, δ ppm): 0.44 (s, 3H, H-8 β-CH3), 1.01 (s, 3H, H-8 α-CH
3), 1.26 (s, 3H, H-4b-CH
3), 1.38～1.62 (m, 5H, H-5 ', 6,7), 2.54 (d, 1H, J=14.5Hz, H-5 "), 2.98 (s, 1H, H-5a), 6.88 (s, 1H, H-1), 7.61 (s, 1H, H-4).
Essence for a better understanding of the present invention, use the The pharmacological results of compound (1)-1, (1)-2, (1)-3, (1)-4, (1)-5, (1)-6, (1)-7, (1)-9, (1)-10, (1)-11, (2)-1, (2)-6, (2)-7, (2)-8, (2)-9, (2)-14, (2)-15, (2)-17, (2)-18, (2)-19, (2)-20, (2)-21 below respectively, its new purposes in pharmacy field is described.
Embodiment 33:MTT method is measured the human cervical carcinoma Hela cell's of (1)-1 pair vitro culture restraining effect
Get the Hela cell that is in logarithmic phase, add an amount of Trypsin liquid digestion, attached cell is come off, the RPMI1640 nutrient solution that contains 10% new-born calf serum with 10ml is made into single cell suspension.The counting back is diluted to the cell suspension of 1 * 105/ml with complete culture solution.Get 96 orifice plates, every hole adds above-mentioned cell suspension 100 μ l, cultivates 24 hours for 37 ℃ in the 5%CO2 incubator.(1)-1 and the DMSO that add 6 concentration successively, each concentration 4 hole.Continue for 37 ℃ to cultivate 48 hours in the 5%CO2 incubator, cultivate the every hole of the preceding 2h of termination and add 1mg/ml MTT100 μ l, continued incubation 4 hours, supernatant liquor is removed in suction, every hole adds the acid DMSO of 150 μ l, shakes up, and measures the OD value of each aperture in the 570nm place with microplate reader.Repeat 3 tests.
The calculation formula of cell survival rate is:
Cell survival rate %=* 100%
Obtain IC with the Bliss method
50
Embodiment 34:MTT method is measured the restraining effect of people's lung cancer A549 cell of (1)-1 pair vitro culture
Get the A549 cell that is in logarithmic phase, add an amount of Trypsin liquid digestion, attached cell is come off, the RPMI1640 nutrient solution that contains 10% new-born calf serum with 10ml is made into single cell suspension.The counting back is diluted to the cell suspension of 1 * 105/ml with complete culture solution.Get 96 orifice plates, every hole adds above-mentioned cell suspension 100 μ l, cultivates 24 hours for 37 ℃ in the 5%CO2 incubator.(1)-1 and the DMSO that add 6 concentration successively, each concentration 4 hole.Continue for 37 ℃ to cultivate 48 hours in the 5%CO2 incubator, cultivate the every hole of the preceding 2h of termination and add 1mg/ml MTT100 μ l, continued incubation 4 hours, supernatant liquor is removed in suction, every hole adds the acid DMSO of 150 μ l, shakes up, and measures the OD value of each aperture in the 570nm place with microplate reader.Repeat 3 tests.
The calculation formula of cell survival rate is:
Cell survival rate %=* 100%
Obtain IC with the Bliss method
50
Obtain the compound activity data of following table three illustrated embodiments 33～embodiment 78 according to similar approach with above embodiment 33,34.
| Embodiment number | Compound number | Hela IC 50，μg/ml a | A549 IC 50，μg/ml |
| 33，34 35，36 37，38 39，40 41，42 43，44 45，46 47，48 49，50 51，52 53，54 55，56 57，58 59，60 61，62 63，64 65，66 67，68 | (1)-1 (1)-2 (1)-3 (1)-4 (1)-5 (1)-6 (1)-7 (1)-9 (1)-10 (1)-11 (2)-1 (2)-6 (2)-7 (2)-8 (2)-9 (2)-14 (2)-15 (2)-17 | 24.3(±0.98) ＞50 ＞50 ＞50 ＞50 ＞50 ＞50 41.5(±0.23) 25.7(±0.06) 27.7(±0.02) 10.9(±0.48) ＞50 42.2(±0.07) 13.4(±0.25) 15.3(±0.97) 18.6(±0.08) ＞50 13.2(±0.04) | 19.6(±0.22) ＞50 ＞50 ＞50 ＞50 ＞50 35.0(±0.33) 41.7(±0.09) 33.8(±0.06) ＞50 5.7(±0.24) ＞50 46.9(±0.15) ＞50 13.7(±0.27) ＞50 36.4(±0.18) 9.6(±0.07) |
| 69，70 71，72 73，74 75，76 77，78 | (2)-18 (2)-19 (2)-20 (2)-21 DDP b | 12.7(±0.13) 16.1(±0.09) 17.6(±0.45) 18.0(±0.09) 5.89(±0.15) | 26.3(±0.08) ＞50 ＞50 25.8(±0.11) 3.58(±0.14) |
a：mean±STD(n＝3)
b: the positive contrast of DDP
Claims (5)
1, a kind of device in category of substitution tricyclo-diterpene-orthodiphenol is characterized in that by geranic acid being that starting raw material synthesizes to come, and all has the chemical structural formula of following formula:
Formula (1)
R wherein
1, R
2Can be to contain substituent benzyl on hydrogen atom or methyl or the aromatic ring; R
3, R
4Can be respectively hydrogen atom, Sauerstoffatom.
2, the described device in category of substitution tricyclo-diterpene-orthodiphenol preparation method of claim 1, this method is shown in figure below:
3, said compound of claim 1 or the said derivative of claim 2, or its pharmacologically acceptable salt or its solvate, it is characterized in that and to combine with auxiliary material or carrier pharmaceutically commonly used to have anti-tumor activity and can be used for anticancer pharmaceutical composition thereby prepare.
4, pharmaceutical composition according to claim 3 is characterized in that it is 0.1%～99.5% that activeconstituents accounts for the gross weight ratio.
5, the application in the medicine of preparation treatment tumour according to compound any in claim 1 or 2 or derivative.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101698645B (en) * | 2009-10-28 | 2013-02-20 | 上海应用技术学院 | Method for synthesizing beta-cyclized ethyl geranate |
| CN104557602A (en) * | 2015-01-07 | 2015-04-29 | 华东师范大学 | Tricyclic diterpene derivative, as well as preparation method and application thereof in preparation of anti-tumour drug |
| WO2016097759A1 (en) * | 2014-12-19 | 2016-06-23 | Aberystwyth University | Anthelmintic compounds |
| CN106928095A (en) * | 2017-03-14 | 2017-07-07 | 华东师范大学 | Cyano group ketene tricyclic diterpene analog and its preparation method and application |
-
2005
- 2005-07-28 CN CN 200510050874 patent/CN1727319A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101698645B (en) * | 2009-10-28 | 2013-02-20 | 上海应用技术学院 | Method for synthesizing beta-cyclized ethyl geranate |
| WO2016097759A1 (en) * | 2014-12-19 | 2016-06-23 | Aberystwyth University | Anthelmintic compounds |
| GB2550750A (en) * | 2014-12-19 | 2017-11-29 | Aberystwyth Univ | Anthelmintic compounds |
| CN104557602A (en) * | 2015-01-07 | 2015-04-29 | 华东师范大学 | Tricyclic diterpene derivative, as well as preparation method and application thereof in preparation of anti-tumour drug |
| CN106928095A (en) * | 2017-03-14 | 2017-07-07 | 华东师范大学 | Cyano group ketene tricyclic diterpene analog and its preparation method and application |
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